NM_015958.3:c.180A>T

Variant names:

• chr1-101021721-T-A
• NM_015958.3:c.180A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_015958.3(DPH5):​c.180A>T​(p.Glu60Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DPH5 NM_015958.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.267
• Publications: 0 publications found

Genes affected

DPH5 (HGNC:24270): (diphthamide biosynthesis 5) This gene encodes a component of the diphthamide synthesis pathway. Diphthamide is a post-translationally modified histidine residue found only on translation elongation factor 2. It is conserved from archaebacteria to humans, and is targeted by diphtheria toxin and Pseudomonas exotoxin A to halt cellular protein synthesis. The yeast and Chinese hamster homologs of this protein catalyze the trimethylation of the histidine residue on elongation factor 2, resulting in a diphthine moiety that is subsequently amidated to yield diphthamide. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DPH5 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• DPH5-related diphthamide-deficiency syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.48136 (below the threshold of 3.09). Trascript score misZ: 0.75264 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08396095).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015958.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH5	NM_015958.3	MANE Select	c.180A>T	p.Glu60Asp	missense	Exon 3 of 8	NP_057042.2	Q9H2P9-1
	DPH5	NM_001077394.2		c.180A>T	p.Glu60Asp	missense	Exon 3 of 8	NP_001070862.1	Q9H2P9-1
	DPH5	NM_001077395.2		c.180A>T	p.Glu60Asp	missense	Exon 3 of 8	NP_001070863.1	Q9H2P9-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH5	ENST00000370109.8	TSL:1 MANE Select	c.180A>T	p.Glu60Asp	missense	Exon 3 of 8	ENSP00000359127.3	Q9H2P9-1
	DPH5	ENST00000427040.3	TSL:1	c.180A>T	p.Glu60Asp	missense	Exon 2 of 7	ENSP00000394364.3	Q9H2P9-1
	DPH5	ENST00000342173.11	TSL:1	c.180A>T	p.Glu60Asp	missense	Exon 3 of 8	ENSP00000339630.7	Q9H2P9-6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.30	N
PhyloP100		0.27
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.054
Sift	Uncertain	0.013	D
Sift4G	Benign	0.64	T
Polyphen		0.016	B
Vest4		0.14
MutPred		0.36		Loss of disorder (P = 0.1593)
MVP		0.53
MPC		0.092
ClinPred		0.89	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.64
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr1-101487277;